NO771717L - PEPTIDE DERIVATIVES AND PROCEDURES FOR THE MANUFACTURE OF THESE - Google Patents

Description

PEPTIDE DERIVATIVES AND METHOD FOR MANUFACTURE THESE.

The present invention relates to new peptide derivatives, particularly those of phosphonic and phosphinic acid, a process for the production of these and pharmaceutical preparations containing these compounds.

The peptide derivatives according to the invention are compounds

where n means 1, 2 or 3,

12 3

R , R and R are the residues of α-amino acids as normal

occurs in proteins with the restriction that R' 3 is never hydrogen and a methyl group when h = 1,

R means hydroxy or methyl and where the configuration on C atom (a) is D, on C atom (b) L and on C atom (c)

2 1

R (if R and R are hydrogen),

and their physiologically tolerable salts.

The term used in the description "residue of an amino acid which normally occurs in the protein" shall mean the residue R of an α-amino acid with the general formula

as it normally occurs in proteins. When, for example, the amino acid is glycine, R constitutes a hydrogen atom and when amino-

the acid is alanine, R constitutes a methyl group. For valine R is an isopropyl group, for leucine an isobutyl group for the glutamic acid 2-carboxyethyl group and for phenylalanine the berizyl group. R can also additionally be bound to an α-amino atom and be part of a nitrogen-containing ring such as proline and in pyroglutamic acid.

In the case that R ^ hydrogen, the configuration on the carbon atom (c) is R, that is the configuration obtained by replacing carboxyl groups in a natural L-amino acid with a phosphorus residue.

When n means 2 or 3 in formula-I, the substituent R 2 can be the same or different α-amino acid residues.

Preferred compounds of formula I are those in which R 4 is a hydroxy group. Equally preferred are compounds of formula I where R is a methyl group as well as compounds in which R 2 is a methyl group and R 3 is a methyl, isopropyl or isobutyl group.

Examples of compounds of formula I are the following: (IR)-1-(D-Alanyl - L-alanylamino)-ethylphosphonic acid, (IR)-1-(D-Alanyl - L-alany 1-^L-alanylamino) - ethylphosphonic acid , (IR) -1-(D-Valyl-L-alanyl-L-^alanylamino)-ethylphosphonic acid , (IR)-1-(D-Leucyl-L-alanyl-L-alanylamino)-ethylphosphonic acid ■ and ( IR)-1-(D-Alanyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid. The peptide derivatives with formula I and their physiologically tolerable salts can be prepared according to the invention by a) cleaving off the protecting group(s) in a compound with the formula in a manner known per se

in which n is as defined above and the configuration at the C atoms (a), (b) and (c) is analogous to those defined above,

R 5 is hydrogen or an amino protecting group,

R , R and R . are residues of the α-amino acids that normally occur in proteins with the analogous limitation as before and by which amino groups may occur. as well as other functional groups are also available in protected form,

40

R is methyl, hydroxy or a lower-4-alkyloxy

protecting group and R hydroxy or a lower alkoxy protecting group, or

b) from an e-n (R, S)-diastereomer mixture of formula I isolates the R-diastereomer in a manner known per se and if

desired transfers an obtained compound of formula I in a physiologically tolerable salt.

One or more of the amino group(s) present in the residues R"<*>"^, R^ and R"^ of the compound of formula II can be in protected form, whereby the amino protecting groups known from peptide chemistry come into play. Particularly suitable amino protecting groups are aralkyloxycarbonyl groups, in particular the benzyloxycarbonyl and tertiary butoxycarbonyl groups. However, the formyl, trityl or trifluoroacetyl residue also comes into play as amino protecting groups. One of the residues R"^,

20 30

R and R in a compound of formula II present carboxy or hydroxy group may be protected by one of the usual carboxyl or hydroxyl protecting groups. A carboxyl group can, for example, be protected by transfer into an alkyl ester or aralkyl ester function, for example a tertiary butyl ester or a benzyl ester. A hydroxy group can, for example, be protected by means of an aralkyloxycarbonyl residue, for example the benzyloxycarbonyl residue, a. alkanoyl residue, for example the acetyl or propionyl residue, an aroyl residue, for example the benzoyl residue, an alkyl residue, for example the tertiary butyl residue, or an aralkyl residue, for example the benzyl residue. The protection of further functional groups which can be parts of the substituents R"^ , 2 0 30'5 R , R , can take place in a known manner. The residue R which is. mentioned as a protecting group in the general formula II, can be any preferably already mentioned amino protecting group i

• connection with the residues R ®, R^ and R"^ before.

The removal of the protective groups in connection with formula II can take place in a known manner, i.e. according to methods which are currently actually used for protection group removal or which are described in the literature. As a result, for example an aralkyloxycarbonyl residue, for example a benzyloxycarbonyl or tert.-butoxycarbonyl group, can be cleaved off hydrolytically, for example by treatment with a mixture of hydrogen bromide and glacial acetic acid. One aralkyloxycarbonyl residue, for example the benzyloxycarbonyl residue, can be cleaved off by hydrogenation, for example in the presence of palladium on charcoal or palladium oxide. Furthermore, the tertiary butoxycarbonyl group can be cleaved off using hydrogen chloride in dioxane. A lower 4 0 41 ° alkoxy group which is present as R and/or R can be straight or branched and preferably contains 1-6 carbon atoms (for example methoxy, ethoxy, propoxy, iso-propoxy, butoxy etc.) and is converted into a • hydroxy group by treatment with a mixture of hydrogen bromide in glacial acetic acid or by means of trimethylchlorosilane and • subsequent aqueous hydrolysis. It is obvious that, depending on the conditions, removal of the protecting group can take place in a single reaction step or in several steps.

The resolution of an R, S-diastereomer compound with the general formula I into its diastereomers and the recovery of the R-diastereomer can be carried out according to known methods, for example by fractional crystallization or by

high pressure liquid chromatography.

The compound of formula I is amphoteric and forms salts with physiologically tolerable strong acids (for example methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid) and physiologically tolerable bases (for example sodium hydroxide).

The output connections with. the general formula II can, for example, be prepared by condensation of a compound with the general formula

where m means 0, 1, 2 or 3 and '

_10 D20D40 _41

, R , R , R . and R as well as the configuration

on the C atoms (b) and (c) are defined as above,

with a suitably protected α-amino acid, a suitably protected di-, tri- or tetrapeptide or a reactive derivative of such a compound in a known manner.

Thus, a compound of formula III with m = 0 can be condensed with a suitably protected dipeptide or a reactive derivative thereof to a compound of formula II with n = 1 or with a suitably protected tripeptide or a reactive derivative thereof to a compound of formula II with n = 2 or with a suitably protected tetrapeptide or a reactive derivative thereof to a compound of formula II with n = 3.

On the other hand, a compound of formula III with m = 1 can be condensed with a suitably protected α-amino acid or a reactive derivative of an α-amino acid to a compound of formula II with n = 1 or with a suitably protected dipeptide or with a reactive derivative thereof to a compound of formula II with. n = 2 or with a suitably protected dipeptide or a reactive derivative, hence to a compound of formula II with n = 3.

A compound of formula III with m = 2 can. however, is also condensed with a suitably protected α-amino acid or reactive derivative thereof to a compound of formula II with.

n = 2 or with a suitably protected dipeptide or a reactive derivative thereof to a compound of formula II with n = 3.

Finally, a compound of formula III with m = 3 can also be condensed with a suitably protected α-amino acid. or a reactive derivative of such an acid to a compound of formula II with n = 3.

On the other hand, the compound of formula II can be prepared by carrying out the previously described condensation using an R,S compound of formula III and isolating the R compound from the obtained R,S product in a known manner, for example by crystallization, chromatography or fractional crystallization or using a suitable base such as α-methylbenzylamine.

The aforementioned condensations can be carried out • according to methods which are well known in peptide chemistry, for example according to the mixed anhydride method, the activated ester, acid or acid chloride method....

According to one of these methods, a suitable compound of formula III can be condensed with a suitably protected α-amino acid or with a suitably protected di-, tri- or tetrapeptide - as desired - whereby the unique carboxyl group is part in a mixed anhydride with an organic or' inorganic acid. Suitably, such an amino acid or such a di-, tri- or tetrapeptide with a free carboxyl group is treated with a tertiary base such as a tri-(lower alkyl)amine, for example triethylamine or with N-ethylmorpholine in an inert organic solvent (for example tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, toluene, petroleum ether or a mixture of these solvents) and the resulting salt is reacted with a chloroacetic acid ester, for example ethyl or iso-butyl ester at low temperature. The mixed anhydride obtained is then suitably condensed in situ with the compound formula III.

According to another method, a suitable compound of formula

III is condensed with an appropriately protected α-amino acid or an appropriately protected di-, tri- or tetrapeptide - as desired - whereby the unique -carboxyl group is present in the form of an acid acid group. This condensation is preferably carried out in an inert organic solvent such as dimethylformamide or ethyl acetate.

by. low temperature.'

According to a further method, a suitable compound of formula III is condensed with a suitably protected α-amino acid or with a suitably protected di-, tri- or tetrapeptide

as desired - , whereby the unique carboxyl group is in the form of an active ester group, for example a ; p-nitrophenyl, 2,4,5-trichlorophenyl or N-hydroxy-succinimide ester group. This condensation is carried out either in an inert organic solvent such as dimethylformamide, or if R 4 0 and/or R 41 are lower alkoxy groups, in an aqueous alkanol, for example aqueous ethanol.

According to a further method, a suitable compound of formula III can be condensed with a suitably protected α-amino acid or with a suitably protected di-, tri- or tetra-peptide - as desired -, whereby the unique carboxyl group is obtained in the form of an acid chloride-. This condensation is preferably carried out in the presence of a base and is carried out at a low temperature.

The peptides according to the present invention potentiate the activity of D-cycloserine. They also have an antibacterial effect against organisms such as Escherichia coli, Klebsiella aerogenes, Streptococcus f.aecalis and Haemophilus influenzae. The compound according to the invention can be used as pharmaceutical preparations with direct or delayed release of active substance in mixture with an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral use such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate ) suspensions or emulsions. Optionally, they are sterilized and respectively or contain further auxiliary substances such as preservatives, stabilisers, cross-linking or emulsifying agents, agents for flavor improvement, salts for changing the osmotic pressure or puffer substances. The preparation of the pharmaceutical preparation can take place in a manner known to each person skilled in the art.

However, the peptide derivatives according to the invention can also be administered in combination with D-cycloserine, and then both in a mixture and in the form of individual components and possibly separately. The amount of the peptide derivative administered, as well as the ratio of the peptide derivative to the D-cycloserine can be varied within wide limits and depends on factors such as the nature of the specific compound, the route of application and the pathogen to be combated. The ratio of peptide derivative to D-cycloserine can for example be 100:1' to 1:100 (weight/weight).

Example 1

4.3 g of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid was added with stirring and backwashing with 4 ml of glacial acetic acid to 12 ml of a 45% solution of hydrogen bromide in glacial acetic acid. The mixture was stirred for 6 hours at room temperature. Then 100 ml of ether was added, the supernatant liquid was decanted and the residue treated with 100 ml of ether. The gum obtained was taken up in 30 ml of methanol. The solution was then treated with 3 ml of propylene oxide in 5 ml of methanol. A white precipitate formed which was allowed to stand overnight at room temperature, was filtered off and washed successively with methanol and ethanol and dried. Crystallization from water/ethanol gave 1.96 g. (IR)-1-(D-Alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid, mp .318° - 320°C (decomposition), [a]^ = -107°

(c = 0.5% in 1'N sodium hydroxide).

The starting material was prepared in the following way:

A solution of 2.7 g of (IR)-1-(L-alanyl-L-alanylamino)-ethylphosphonic acid in 50 ml of water was added with stirring at 5°C with 2.0 g of triethylamine and 50 ml of ethanol. The resulting clear solution was cooled to 0°C and mixed with 3.8 g of solid N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-alanine and 25 ml of ethanol. The mixture was stirred for 2 hours at 0°C and 16 hours at room temperature. The clear solution was evaporated and the residue partitioned between 150 ml of water and 100 ml of chloroform. The aqueous solution was again washed with 100 ml of chloroform and the organic phase with 50 ml of water. The combined aqueous extracts were evaporated, the residue was taken up in a mixture of 40 ml of water and 40 ml of methanol and passed through a freshly regenerated column of cation exchange resin. It was eluted with a mixture of water and methanol (1:1, v/v). The eluate was evaporated and the residue taken up with 250 ml of water. The aqueous solution was extracted twice with 100 ml of ether, the ether extract was washed with 50 ml of water and the combined aqueous extracts were then evaporated to approx. 100 ml. The same amount of methanol was added and the resulting solution titrated with 1 M aqueous benzylamine to a pH of 4.5. The solution was evaporated to dryness and the residue recrystallized from 100 ml of hot water to which was added 400 ml of ethanol and 500 ml of ether. 4.38 g of the benzylamine salt of (IR)-1-[(N-benzyloxycarbonyl-D-alanyl-L-alanyl-L-alahyl)-amino]-ethylphosphonic acid were obtained, melting point 240° - 243°C (decomposition), = ~38.1° (c = 0.53% in acetic acid).

Example 2

In an analogous manner to example 1, obtained from the benzylamine salt of (IR)-1-[(N-benzyl.oxycarbonyl-D-valyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid (IR)-1-(D -Valyl-L-alanyl-L-alanylaminoj-ethylphosphonic acid, melting point 301° -304° C. (decomposition), [ot]D= -105° (c = 0.45% in 1 N sodium hydroxide) ..

The starting material was prepared as follows:

3.8 g of N-benzyloxycarbonyl-D-valine in 200 ml of petroleum ether (boiling point 60°-80°C) was mixed with stirring and cooling at -5°C with 1.5 g of triethylamine. After adding 2.1 g of chloroformic acid isobutyl ester, the mixture was further cooled for 30 minutes to -5°C. Then, at -5°C, a solution of 2.7 g of (IR)-1-(L-Alanyl-L-alanylamino)-ethylphosphonic acid in a mixture of 2.0 g of triethylamine and 15 ml of water, as well as a further 5 ml water added. It was further stirred for 2 hours at -5° to 0°C and overnight at room temperature. After addition of 150 ml of water, the aqueous phase was separated, evaporated, the residue was taken up in a mixture of 40 ml of water and 40 ml of methanol and passed through a column with a freshly regenerated cation exchanger based on a sulphonated polystyrene resin. The column was eluted with a 1:1 mixture of water and methanol, the eluate evaporated and taken up 5 times in 50 ml of water and evaporated again.' The residue was finally treated with 100 ml of ether, filtered off and dissolved in a mixture of -400 ml of methanol ■ and 400 ml of water. The solution was titrated with 4 M aqueous benzylamine to a pH of 4.5 and evaporated to dryness. The residue obtained was recrystallized from a mixture. of 100 ml of methanol and 100 ml of ether and ga- 3.24. g of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-D-valyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid, melting point 238° 244°C (decomposition).

Example 3

In an analogous manner to that in example 1 was obtained from the benzylamine salt

of (1R)-1-[(N-benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid (IR)-1-(D-Alanyl-L-alanyl-L -alanyl-L-alanylamino)-ethylphosphonic acid, mp 323°-325°C (dec.), [α]^ -121° (g = 0.48% in 1 N sodium hydroxide) prepared.

The starting material was produced in the following way:

In an analogous manner to example 1, from the N-hydroxysuccinimide ester of N-benzyloxycarbonyl 1-L-alanine and (IR)-1-(L-Alanyl-L-alanylamino)-ethylphosphonic acid (IR)-1-[( N-benzyloxycarbonyl-L-alanyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid, mp 255°-257°C (decomposition), fa]^0 = -62.0° (c 0.4% in glacial acetic acid), prepared.

This compound was then likewise transferred in an analogous manner" as in example 1 into (IR)-1-[(N-benzyloxycarbonyl-L-alanyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid, melting point 312° 313° C (decomposition), [a]^° = -101° (c 0.53% in-1 N sodium hydroxide) .

Finally, in an analogous way as in example 1, but below, acidification to pH was carried out. 2 and by replacing the ion exchange with subsequent ether extraction for a simple ether extraction, the benzylamine salt obtained from (IR)-1-[(N-benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl-L-alanyl)-amino ]-ethylphosphonic acid, melting point 272°-277° C (decomposition), [a]^<0>= -47.0° (c = 0.5% in acetic acid), from the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D -alanine and (IR)-1-(L-Alanyl-L-alanyl-L-alanyl-amino)-ethylphosphonic acid.

Example 4

10.85 g of (IR)-1-[(N-benzyloxycarbonyl-D-leucyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid dimethyl ester was dissolved in 30 ml of a 35% solution of hydrogen bromide in glacial acetic acid . The mixture

was stirred for 4 hours at room temperature and mixed with further stirring with 130 ml of ether. The ether was then decanted and this procedure was repeated twice more using

80 ml of ether. The residue was dissolved in 70 ml of methanol and the resulting solution was mixed with 10 ml of propylene oxide and stored overnight in a refrigerator. The precipitate obtained was filtered off, washed with ethanol and ether and dried under reduced pressure to a constant weight of 7.99 g, melting point 293°-295°C (decomposition). • Recrystallization from 500 ml cold water and 700 ml ethanol

gave 6.67 g. (IR)-1-(D-Leucyl-L-alanyl-L-alanylamino)-ethylphosphonic acid» m.p. 300°-320°C (dec.), [alj^ = -129.3°

(c = 1% in water).

The starting material was prepared in the following way:

12.9 g of (IR)-1-t.(N-benzyloxycarbonyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid dimethyl ester was dissolved in 150 ml of methanol with a content of 0.032 mol of hydrogen fluoride. The solution was hydrated at room temperature under normal pressure in the presence of 1 g of 10% Pd/C catalyst, the catalyst was filtered off, the filtrate evaporated under reduced pressure and the oily hydrochloride evaporated twice with ethyl acetate.

The product obtained and 10.9 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-leucine were stirred in the presence of 100 ml of dry dimethylformamide. At a temperature below 15°, 4.2 ml became dry. triethylamine added dropwise with stirring., The mixture was then stirred overnight at room temperature, the triethylamine hydrochloride filtered off and the filtrate evaporated under oil pump vacuum at a bath temperature below 40°C. The residual oil was treated with 50 ml of water and the resulting mixture extracted 4 times with 50 ml of chloroform. The combined organic phases were washed with 20% potassium carbonate solution and dried over sodium sulfate. After evaporation to dryness and evaporation twice with ethyl acetate, 15.5 g of (IR)-1-[(N-benzyloxycarbonyl-D-leucyl-L-alanyl-L-alanyl)-amino]-ethylphosphonic acid dimethyl ester were obtained, the melting point of which after recrystallization ion from acetonitrile was 173°-176°C, E01]^<0>=

-36.6° (c = 1% in methanol) .

Example 5:

In an analogous manner to example 4, 9.92 g of (1~ R)-1-[(N-benzyl 1-oxycarbonyl-D-alanyl-L-alanyl)-amino]-ethylphosphonic acid dimethyl ester was treated with 45 ml of a 35% solution of hydrogen bromide in acetic acid. Analogous work-up gave 6.16 g of a crude product with a melting point of 282°-285°C and after recrystallization from water/ethanol 5.47 g of pure (IR)-1-(D-Alanyl-L-alanyl-amino) -ethylphosphonic acid, melting point 292°-293°C (decomposition), [a]^° -101.2° (c '= 1% in water) .

The starting material, (IR)-1-[(N-benzyloxycarbonyl-D-alanyl-L-alanyl)-amino]^ethylphosphonic acid dimethyl ester, mp 115°-117°C, [α]p° -28.4° (c - 0.5% in methanol), yield: 11.1 g was prepared in an analogous manner to example 4 by reacting 7.82 g of (IR)-1-(L-Alanylamino)-ethylphosphonic acid dimethyl ester hydrochloride with 9 .6 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-alanine.

The following example illustrates a typical pharmaceutical preparation with a content of the compound according to the invention:

Example 6

1000 ml of an injection solution with the following composition was prepared:

Manufacturing:

The (IR)-1-(D-Alanyl-L-alanylamino)-ethylphosphonic acid was up-

diluted in 500 ml of water for injections. This solution was

put a' solution of chlorocresol in 200 ml of water for injections.

Then, while stirring, the acetic acid was added, as well as 0.1 N sodium hydroxide solution. to a pH of 4.5. Finally, it was filled up to 1000 ml with water, filtered through a sterile membrane filter (0.22^) and filled into ampoules. The ampoules were closed and sterilized in an autoclave for 20 minutes at 121°C.

Claims (19)

1. Procedure for the production of peptide derivatives with the general formula where n means 1, 2 or 3, R 1, R 2 and R 3 are the residues of α-amino acids that normally occur in proteins, with the restriction that R <3> is never hydrogen and a methyl group, when'n =1, 4 R means hydroxy or methyl and whereby the configuration on C atom (a) is D, on C atom (b) is L and' on C atom (c) is R (provided R 2 and R 1^ are hydrogen) . and of physiologically tolerable salts of these, the compounds, characterized in that one a) cleaves off the protecting group(s) in a known manner in connection with the formula where n is defined as above and the configurations -on the C atoms (a), (b) and (c) are analogous to above, R hydrogen or an amino protecting group, „10 D20 _30 R , R and R the residues of α-amino acids which normally occur in proteins with the above analogous restriction and whereby any amino groups present may be present in a protected form, as well as other functions ■national groups, if necessary, also exist in a protected form, 40 R. means methyl, hydroxy or a lower- 41 protecting group and R hydroxy or a lower alkoxy protecting group, or b). from. a (R,'S)-diastereomer mixture of formula I isolates the R-diastereomer in a known manner and optionally transfers an obtained compound of formula I in a physiologically tolerable salt. 2. Method according to claim 1, characterized in that a peptide derivative of formula I is prepared, in which R<4> is a hydroxyl group. 3. Method according to claim 1 or 2, characterized in that a peptide derivative of formula I is prepared, where R is a methyl group. 4. Method according to one of claims 1-3, characterized in that a peptide derivative 2 3 of formula I is prepared, in which R is a methyl group and R is a methyl, isopropyl or isobutyl group.. 5. Process according to claim 1, characterized in that (IR)-1-(D-Alanyl-L-alanylamino)-ethylphosphonic acid is produced. 6. Process according to claim 1, characterized in that (IR)-1-(D-Alanyl-L-alanyl-L-alanyl-amino)-ethylphosphonic acid is produced. 7. Process according to claim 1, characterized in that (IR)-1-(D-Valyl-L-alanyl-L-alanyl-amino)-ethylphosphonic acid is produced. 0. Method according to claim 1, characterized in that (IR)-1-(D-Leucyl-L-alanyl-L-alanyl-amino)-ethylphosphonic acid is produced. 9. Method according to claim 1, characterized in that one prepares (IR)-1-(D-Alany1-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid. 10. Method according to claim 1, characterized in that the starting compound with formula II is prepared by condensation of a compound with the general formula where m means 0, 1, 2 or 3 and R^, R^ ®, R^ and R^ as well as the configuration of the C atoms (b) and (c) are defined as in claim 1, with a suitably protected α-amino acid, a suitably protected di-, tri- or tetrapeptide or a reactive derivative of such a compound. known way. 11. Procedure for the manufacture of pharmaceutical preparations rates, characterized by mixing a compound with formula I according to claim 1 or a "physiolo give a tolerable salt of such a compound as active ingredient with non-toxic, inert, solid or liquid carriers suitable for therapeutic administration, usual in such preparations, and bring the resulting mixture into a suitable galenic form. •. 12. Process for the production of pharmaceutical preparations, characterized by mixing a compound of formula I according to claim 1 or a physiologically tolerable salt of such a compound and D-cycloserine as active ingredients with non-toxic, inert, suitable for therapeutic administration, in such preparations usual, solid or liquid carriers and brings the resulting mixture into a suitable galenic form. 13. Pharmaceutical preparations, characterized by a content of a peptide derivative of formula I according to claim 1 and a non-toxic, inert, solid or liquid carrier suitable for therapeutic administration. 14. Pharmaceutical preparations, characterized by a content of a peptide derivative with formula I according to claim 1 and D-cycloserine as well as a for therapeutic administration suitable, non-toxic, inert, solid or liquid carrier. 15. A compound with the general formula where n means 1, 2 or 3, 5 R hydrogen or an amino protecting group, D10 ^20^30, . n. R , R and R the residues of α-amino acids that usually occur in proteins, with the restriction that R never is hydrogen and one. methyl group reaches n 1, and whereby any amino groups that may occur as well as other functional groups are possibly present in a protected form, 40 R is methyl, hydroxy or a lower-41 alkoxy protecting group and R is hydroxy or a lower- protecting group and the configuration on the G atom (a) is D, on the C atom (b) is L and on the C atom (c) is R (provided R and R"^ ^ ^ hydrogen) . 16. ' The peptide derivative of the general formula where n means 1, 2 or 3, 12 3 R , R and R the residues of α-amino acids that normally occur in proteins with the restriction that R <3> is never hydrogen and a methyl group when n = 1, 4 R means hydroxy or methyl and whereby the configuration on C atom (a) is D, on C atom (b) is L and 2 1 ■on C atom (c) is R (provided R and R y hydrogen), and physiologically tolerable salts of these compounds. 17. Peptide derivatives according to claim 16, characterized by 4 characterized by R being a hydroxy group.. 18. Peptide derivatives according to claim 16 or 17, k a r a k - 4 characterized in that R is a hydroxy group. 19. Peptide derivatives according to one of claims 16-18, characterized in that R 2 is a methyl group and R 3 is a methyl, isopropyl or isobutyl group. 20. (IR)-1-(D-Alanyl-L-alanylamino)-ethylphosphonic acid. 21. (IR)-1-(D-Alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid. 22. (IR)-1-(D-Valyl-L-alanyl-L-alanylamino)-ethylphosphonic acid. 23. ■ (IR)-1-(D-Leucyl-L-alanyl-L-alanylamino)-ethylphosphonic acid. 24. (IR)-1-(D-Alanyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid.